Congenital anorchia represents a rare form of testicular disorder. It classically refers to the absence of unilateral or bilateral testes in an otherwise normal genetic male. It is usually diagnosed in infancy due to the absence of testes with or without evidence of micropenis during routine health screening of the child. However, it can be identified at late stages while the person is being evaluated for delayed puberty and primary hypogonadism. Early identification and differentiation from cryptorchidism are essential from a therapeutic point of view. Apart from imaging studies, hormonal evaluation plays a crucial role in establishing the diagnosis.

Bilateral congenital anorchia is a rare condition. This is also referred to as testicular regression syndrome or vanishing testis syndrome. The condition is defined as the absence of testis in a 46, XY individual with male phenotype.[1] The prevalence of this disorder is estimated to be 1 in 20,000 male births.[2] The patients usually present with a normal male phenotype, but presentation of ambiguous external genitalia or microphallus has been described.[3],[4] Congenital anorchia has to be differentiated from bilateral cryptorchidism which is much more commonly seen in clinical practice as clinical outcome and management strategies are significantly different for these entities. Herein, we discuss the presentation of two cases of congenital anorchia with a brief review of the relevant literature.

Case Reports

Case 1

A 28-year-old male presented for evaluation of small-sized phallus and nondevelopment of secondary sexual characteristics. On inquiry, parents gave a history of the absence of bilateral testicles from the scrotal sac since birth. There was no history of testicular trauma, torsion, mumps orchitis, inguinal surgery, head trauma, cranial irradiation, or any neurosurgical procedures. There was no history suggestive of any other pituitary hormone deficiency. The patient had received 5 monthly injections of testosterone 1 year back by consulting his primary physician. However, he had discontinued all medications for the past 12 months. Clinical evaluation showed a height of 180 cm, body mass index 22.34 kg/m 2, and presence of eunuchoid body proportions. There was the presence of a grossly hypoplastic scrotum without any testes and microphallus with a stretched penile length (SPL) of 3 cm [Figure 1]a. Ultrasonography of abdomen, pelvis, and scrotal sac failed to reveal any testis-like structures. The same was also confirmed by magnetic resonance imaging (MRI) of abdomen, pelvis, and inguinoscrotal region which could not identify any testicular remnants. Complete blood count, liver function test, renal function tests, and serum electrolytes were within normal limit. The hormonal parameters are summarized in [Table 1]. Karyotype analysis revealed a normal 46, XY pattern. Based on above clinical findings and corroborative hormonal parameters, a diagnosis of congenital bilateral anorchia was made. He was started on testosterone replacement therapy and is on regular follow-up.

Figure 1: (a and b) Presence of micropenis and hypoplastic scrotum without testicles

A 15-year-old male was brought by his parents for evaluation of nondevelopment of secondary sexual characteristics and a small-sized phallus. On inquiry, the patient did not have any history of testicular trauma, torsion, mumps orchitis, inguinal surgery, head trauma, cranial irradiation, or any neurosurgical procedures. The parents had noticed the absence of palpable testicles since birth. There was no history suggestive of any other pituitary hormone deficiency. Clinical evaluation showed a prepubertal sexual maturity status (Tanner staging P1 G1). He also had evidence of micropenis with a SPL of 2.8 cm, poorly developed scrotum, and absence of bilateral testes in scrotal sac [Figure 1]b. Ultrasonography and MRI of abdomen, pelvis, and scrotal sac failed to reveal any testicular tissue. Complete blood count, liver function test, renal function tests, and serum electrolytes were within normal limit. The hormonal parameters are summarized in [Table 1]. The patient had undergone a laparoscopic exploration before presenting to us, which failed to detect any testicular remnants. Karyotype revealed a normal male type 46, XY pattern. A diagnosis of congenital bilateral anorchia was thus confirmed. Low-dose testosterone therapy with gradual escalation was started for inducing appropriate pubertal changes.

Discussion

As described earlier, there is a complete absence of testicular tissue in bilateral congenital anorchia. Bilateral cryptorchidism also presents with the absence of palpable testicles within the scrotal sac. Hence, the two entities can be frequently confused. The exact etiology of bilateral congenital anorchia is yet to be clearly elucidated. The patients with bilateral anorchia have a normal male phenotype without the presence of Mullerian structures. Hence, fetal testes must have been present during early development (8–16 weeks gestation), producing sufficient androgen levels for normal or moderate abnormal development of the external male genitalia and adequate anti-Mullerian hormone (AMH) to permit disappearance of the uterus, Fallopian tube More Detailss, and upper vagina.[1],[4] Based on above findings, it is highly likely that testicular regression syndrome occurs during late fetal life in this condition although regression of the testes in early infancy has also been described in a number of cases.[5]

Mechanical causes as the possible etiology of anorchia include testicular torsion, trauma, or vascular occlusion of spermatic structures.[5] The presence of histopathological features of hemosiderin-laden macrophages and foci of dystrophic calcification showed a positive association with testicular regression syndrome. The findings are being consistent with changes secondary to intrauterine testicular torsion.[6] The possibility of genetic origin of bilateral anorchia has also been recently explored by various authors as a number of familial cases of bilateral anorchia have been described.[5],[7] The occurrence of anorchia with 46, XY genital ambiguity within families supports the hypothesis that some forms of this condition may be a part of the clinical spectrum of 46, XY gonadal dysgenesis.[5]

In a large series of anorchia cases (n = 26), Brauner et al. did not identify any mutations in insulin-like 3, steroidogenic factor 1 (NR5A1), Y chromosome-linked testis-determining gene (SRY), the T222P variant for Leucine-rich repeat-containing G-protein-coupled receptor 8(LGR8), and mastermind-like domain-containing 1.[7] Hence, they concluded that mutations among these do not contribute to the development of anorchia and other genetic factors may play a role. However, in another similar large French series, the authors identified one affected individual with anorchia who carried a heterozygous NR5A1 mutation (p.V355M).[5]

Hormonal evaluations are quite helpful in diagnosing cases of anorchia. Undetectable plasma concentrations of AMH and inhibin B and an elevated plasma follicle-stimulating hormone, together with 46, XY complement, are sufficient for its diagnosis.[7] Absence of testosterone response to human chorionic gonadotropin test is predictive of the absence of testes. AMH level is more sensitive than testosterone level but is equally specific for the condition. Treatment with low doses of testosterone at pubertal age leads to a normal adult height. The very low or undetectable plasma AMH and inhibin B concentrations seem to be a good biological marker of anorchia.[7] In boys with bilateral vanished testes, gonadotropins and inhibin B levels are significantly different from that of bilateral cryptorchid boys. If such a pattern of abnormal hormonal values is obtained from boys with bilateral nonpalpable testes, tubular tissue is not present, and surgery can be avoided.[8] Especially, the discriminative value of AMH in cases of bilateral anorchia is so high that an undetectable AMH in such a case may avoid the need for invasive surgical exploration.[9]

In boys with bilateral vanished testes, gonadotropins and inhibin B levels are significantly different from that of bilateral cryptorchid boys. If such a pattern of abnormal serum values is obtained from boys with bilateral nonpalpable testes, tubular tissue is not present, and surgery can be avoided.[8] It is well known that significant risk of gonadal malignancy exists for patients with cryptorchidism, especially with intra-abdominal testis. On the contrary, the infrequent finding of seminiferous tubules or other germinal tissues in the surgical specimens of patients with inguinal vanishing testes also supports the contention that the risk of malignant degeneration is quite low in this population.[10] In the case of TRS, most of the authors agree that the testicular remnants (if any) are not associated with germline neoplasia.[9]

Conclusion

Congenital anorchia is a rare condition which should be strictly differentiated from bilateral cryptorchidism due to different clinical course and management strategies for these conditions. It can be readily diagnosed with a distinctive hormonal pattern of elevated gonadotropins, low AMH, and low inhibin levels in a 46, XY individual without surgical intervention. Knowledge about this entity is pivotal for physicians and surgeons caring for such patients for early diagnosis and appropriate management.

Declaration of patient consent

The authors have obtained necessary informed consent from the patient and/or parents/guardian for publication of photographs.

Acknowledgment

The authors would like to thank all the patients and their family members for their cooperation.